Ultrasound contrast agent microbubbles are composed of a variety of gases and stabilizing shell materials. FDA-approved applications of ultrasound contrast agents are currently limited to cardiography, and while their diagnostic utility is well-established, significant improvements could lead to increased clinical applications. In addition, the potential of cavitation-related bioeffects for therapeutic applications is exciting, and has received considerable recent attention;e.g., to facilitate targeted drug delivery or to enhance gene therapy, where changes in the vascular endothelium or cell membrane permeability are thought to be critical. The diagnostic and therapeutic effects of ultrasound contrast agents depend on the dynamical responses to the applied acoustic fields insonifying these microbubbles, either contained within the stabilizing shell, or in the form of free gas bubbles liberated from the contrast agent. The long-range objective of this project is to understand those responses and the permeabilizing effects they have on the vascular endothelium, so as to permit a rational exploitation of ultrasound-contrast-agent-enhanced cavitation. We propose to study bubble responses of ultrasound contrast agents in unconstrained media in-vitro, and in in-vivo intestinal mesentery blood vessels and ear veins. Bubble dynamics will be measured with laser light scattering and high-speed imaging, while cavitation will be measured with passive and active cavitation detectors. The biological effects of cavitation on the vascular endothelium will be examined through histology. Accordingly, the three specific aims of this project are as follows: (1) To image and to analyze the interaction of imaging and therapeutic ultrasound pulses with individual and clustered UCA microbubbles in vitro;(2) to assess cavitation in response to acoustic parameters for imaging and therapeutic applications;and (3) to determine how the constrained intravascular environment affects microbubble response ex vivo, and to determine its association with vascular permeabilization in vivo. This research is relevant to public health because understanding the interaction of ultrasound with designer bubbles will lead to improvements in medicine. These improvements will include a better diagnosis of medical problems, and therapeutic applications, such as delivery of drugs and medicine.